Am. J. Hum. Genet. 77:519–532, 2005
REVIEW ARTICLE
The Use of Racial, Ethnic, and Ancestral Categories in Human Genetics
Research
Race, Ethnicity, and Genetics Working Group*
National Human Genome Research Institute, Bethesda
The global dispersal of anatomically modern humans over the past 100,000 years has produced patterns of phenotypic variation that have exerted—and continue to exert—powerful influences on the lives of individuals and
the experiences of groups. The recency of our common ancestry and continued gene flow among populations have
resulted in less genetic differentiation among geographically distributed human populations than is observed in
many other mammalian species. Nevertheless, differences in appearance have contributed to the development of
ideas about “race” and “ethnicity” that often include the belief that significant inherited differences distinguish
humans. The use of racial, ethnic, and ancestral categories in genetics research can imply that group differences
arise directly through differing allele frequencies, with little influence from socially mediated mechanisms. At the
same time, careful investigations of the biological, environmental, social, and psychological attributes associated
with these categories will be an essential component of cross-disciplinary research into the origins, prevention, and
treatment of common diseases, including those diseases that differ in prevalence among groups.
Introduction
Human genetics research is generating unprecedented
amounts of data about the genetic differences among
individuals and groups. Investigation of these differences
will transform our understanding of the origins and nature of human diseases (Collins et al. 2003).
Research into human genetic differences also has the
potential to generate great controversy. In the past, concepts drawn from genetics have been used—both by geneticists and by individuals outside the field—to justify
and perpetuate racial and ethnic discrimination (Kevles
1985; Provine 1986). The belief that racial and ethnic
groups have substantial, well-demarcated biological differences and that these differences are important has
contributed to many of the great atrocities of the 20th
century and continues to shape personal interactions
and social institutions (Mosse 1985; Shipler 1997). Because of the history of misuse of genetics ideas, geneticists have a special responsibility to examine carefully
their use of racial and ethnic categories in their research.
Received October 20, 2004; accepted for publication July 27, 2005;
electronically published August 29, 2005.
Address for correspondence and reprints: Steve Olson, 7609 Sebago
Road, Bethesda, MD 20817. E-mail: [email protected]
* The Race, Ethnicity, and Genetics Working Group of the National
Human Genome Research Institute includes Kate Berg, Vence Bonham,
Joy Boyer, Larry Brody, Lisa Brooks, Francis Collins, Alan Guttmacher,
Jean McEwen, Max Muenke, Steve Olson, Vivian Ota Wang, Laura
Lyman Rodriguez, Nadarajen Vydelingum, and Esther Warshauer-Baker.
This article is in the public domain, and no copyright is claimed.
0002-9297/2005/7704-0002
Investigations that fail to recognize and acknowledge
the full range of mechanisms through which designations of race, ethnicity, and ancestry can correlate with
personal traits and health outcomes threaten to reinforce widely held stereotypes. Yet genetics research also
has the potential, by delineating the complex origins of
traits and the close biological affinities between human
groups, to help dispel these stereotypes.
The sequencing of the human genome (International
Human Genome Sequencing Consortium 2001; Venter
et al. 2001) and the ongoing international effort to catalog common haplotypes in several populations (International HapMap Consortium 2003) make this an opportune time to examine the complex relationships between genetics research and the categories of race, ethnicity, and ancestry. Although such a review inevitably
draws on very different academic disciplines and literatures, a cross-disciplinary conversation is essential for
reconciliation of the promise of genetics research with
the historical and potential abuses of ideas drawn from
genetics. This review summarizes what is known about
patterns of human genetic variation; the historical development of widely held conceptions about race, ethnicity, and ancestry; and the interactions between these
conceptions and human genetics research.
The Origins, Patterns, and Physical Manifestations
of Human Genetic Variation
The Origins of Modern Humans
Information about the history of our species comes
from two main sources: the paleoanthropological record
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and historical inferences based on current genetic differences observed in humans. Although both sources of
information are fragmentary, they have been converging
in recent years on the same general story.
The existing fossil evidence suggests that anatomically modern humans evolved in Africa, within the last
∼200,000 years, from a pre-existing population of humans (Klein 1999). Although it is not easy to define
“anatomically modern” in a way that encompasses all
living humans and excludes all archaic humans (Lieberman et al. 2002), the generally agreed-upon physical
characteristics of anatomical modernity include a high
rounded skull, facial retraction, and a light and gracile,
as opposed to heavy and robust, skeleton (Lahr 1996).
Early fossils with these characteristics have been found
in eastern Africa and have been dated to ∼160,000–
200,000 years ago (White et al. 2003; McDougall et al.
2005). At that time, the population of anatomically
modern humans appears to have been small and localized (Harpending et al. 1998). Much larger populations
of archaic humans lived elsewhere in the Old World,
including the Neandertals in Europe and an earlier species of humans, Homo erectus, in Asia (Swisher et al.
1994).
Fossils of the earliest anatomically modern humans
found outside Africa are from two sites in the Middle
East and date to a period of relative global warmth,
∼100,000 years ago, though this region was reinhabited
by Neandertals in later millennia as the climate in the
northern hemisphere again cooled (Lahr and Foley 1998).
Groups of anatomically modern humans appear to have
moved outside Africa permanently sometime 160,000
years ago. One of the earliest modern skeletons found
outside Africa is from Australia and has been dated to
∼42,000 years ago (Bowler et al. 2003), although studies
of environmental changes in Australia argue for the presence of modern humans in Australia 155,000 years ago
(Miller et al. 1999). To date, the earliest anatomically
modern skeleton discovered from Europe comes from
the Carpathian Mountains of Romania and is dated to
34,000–36,000 years ago (Trinkaus et al. 2003).
Existing data on human genetic variation support and
extend conclusions based on the fossil evidence. African
populations exhibit greater genetic diversity than do
populations in the rest of the world, implying that humans appeared first in Africa and later colonized Eurasia
and the Americas (Tishkoff and Williams 2002; Yu et
al. 2002; Tishkoff and Verrelli 2003). The genetic variation seen outside Africa is generally a subset of the variation within Africa, a pattern that would be produced if
the migrants from Africa were limited in number and
carried just part of African genetic variability with them
(Cavalli-Sforza and Feldman 2003). Patterns of genetic
variation suggest an earlier population expansion in Af-
Am. J. Hum. Genet. 77:519–532, 2005
rica followed by a subsequent expansion in non-African
populations, and the dates calculated for the expansions
generally coincide with the archaeological record (Jorde
et al. 1998).
Aspects of the relationship between anatomically modern and archaic humans remain contentious. Studies of
mtDNA (Ingman et al. 2000), the Y chromosome (Underhill et al. 2000), portions of the X chromosome (Kaessmann et al. 1999), and many (though not all) autosomal
regions (Harpending and Rogers 2000) support the “Out
of Africa” account of human history, in which anatomically modern humans appeared first in eastern Africa
and then migrated throughout Africa and into the rest
of the world, with little or no interbreeding between
modern humans and the archaic populations they gradually replaced (Tishkoff et al. 2000; Stringer 2002). However, several groups of researchers cite fossil and genetic
evidence to argue for a more complex account. They contend that humans bearing modern traits emerged several
times from Africa, over an extended period, and mixed
with archaic humans in various parts of the world (Hawks
et al. 2000; Eswaran 2002; Templeton 2002; Zie˛tkiewicz
et al. 2003). As a result, they say, autosomal DNA from
archaic human populations living outside Africa persists
in modern populations, and modern populations in various parts of the world still bear some physical resemblance to the archaic populations that inhabited those
regions (Wolpoff et al. 2001).
However, distinguishing possible contributions to the
gene pool of modern humans from archaic humans outside Africa is difficult, especially since many autosomal
loci coalesce at times preceding the separation of archaic
human populations (Pääbo 2003). In addition, studies
of mtDNA from archaic and modern humans and extant
Y chromosomes suggest that any surviving genetic contributions of archaic humans outside Africa must be
small, if they exist at all (Krings et al. 1997; Nordborg
1998; Takahata et al. 2001; Serre et al. 2004). The observation that most genes studied to date coalesce in
African populations points toward the importance of
Africa as the source of most modern genetic variation,
perhaps with some subdivision in the ancestral African
population (Satta and Takahata 2002). Sequence data
for hundreds of loci from widely distributed worldwide
populations eventually may clarify the population processes associated with the appearance of anatomically
modern humans (Wall 2000), as well as the amount of
gene flow among modern humans since then.
The Distribution of Variation
A thorough description of the differences in patterns
of genetic variation between humans and other species
awaits additional genetic studies of human populations
Race, Ethnicity, and Genetics Working Group: Racial and Ethnic Categories in Genetics
and nonhuman species. But the data gathered to date
suggest that human variation exhibits several distinctive
characteristics. First, compared with many other mammalian species, humans are genetically less diverse—a
counterintuitive finding, given our large population and
worldwide distribution (Li and Sadler 1991; Kaessmann
et al. 2001). For example, the chimpanzee subspecies
living just in central and western Africa have higher levels of diversity than do humans (Ebersberger et al. 2002;
Yu et al. 2003; Fischer et al. 2004).
The distribution of variants within and among human
populations also differs from that of many other species.
The details of this distribution are impossible to describe
succinctly because of the difficulty of defining a “population,” the clinal nature of variation, and heterogeneity
across the genome (Long and Kittles 2003). In general,
however, 5%–15% of genetic variation occurs between
large groups living on different continents, with the remaining majority of the variation occurring within such
groups (Lewontin 1972; Jorde et al. 2000a; Hinds et al.
2005). This distribution of genetic variation differs from
the pattern seen in many other mammalian species, for
which existing data suggest greater differentiation between groups (Templeton 1998; Kittles and Weiss 2003).
Our history as a species also has left genetic signals
in regional populations. For example, in addition to having higher levels of genetic diversity, populations in Africa tend to have lower amounts of linkage disequilibrium than do populations outside Africa, partly because
of the larger size of human populations in Africa over
the course of human history and partly because the number of modern humans who left Africa to colonize the
rest of the world appears to have been relatively low
(Gabriel et al. 2002). In contrast, populations that have
undergone dramatic size reductions or rapid expansions
in the past and populations formed by the mixture of
previously separate ancestral groups can have unusually
high levels of linkage disequilibrium (Nordborg and Tavare 2002).
Many other geographic, climatic, and historical factors have contributed to the patterns of human genetic
variation seen in the world today. For example, population processes associated with colonization, periods of
geographic isolation, socially reinforced endogamy, and
natural selection all have affected allele frequencies in
certain populations (Jorde et al. 2000b; Bamshad and
Wooding 2003). In general, however, the recency of our
common ancestry and continual gene flow among human groups have limited genetic differentiation in our
species.
Substructure in the Human Population
Although the genetic differences among human groups
are relatively small, these differences nevertheless can be
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used to situate many individuals within broad, geographically based groupings. For example, computer analyses
of hundreds of polymorphic loci sampled in globally distributed populations have revealed the existence of genetic
clustering that roughly is associated with groups that historically have occupied large continental and subcontinental regions (Rosenberg et al. 2002; Bamshad et al.
2003).
Some commentators have argued that these patterns
of variation provide a biological justification for the use
of traditional racial categories. They argue that the continental clusterings correspond roughly with the division
of human beings into sub-Saharan Africans; Europeans,
western Asians, and northern Africans; eastern Asians;
Polynesians and other inhabitants of Oceania; and Native Americans (Risch et al. 2002). Other observers disagree, saying that the same data undercut traditional
notions of racial groups (King and Motulsky 2002; Calafell 2003; Tishkoff and Kidd 2004). They point out, for
example, that major populations considered races or subgroups within races do not necessarily form their own
clusters. Thus, samples taken from India and Pakistan
affiliate with Europeans or eastern Asians rather than
separating into a distinct cluster. However, samples from
the Kalash, a small population living in northwestern
Pakistan, form their own cluster on a level comparable
with those of the major continental regions (Rosenberg
et al. 2002).
Sampling design can have a critical influence on the
results of such studies. Studies of genetic clustering often
have relied on samples taken from widely separated and
socially defined populations. When samples were analyzed from individuals who were more evenly distributed
geographically, clustering was far less evident (Serre and
Pääbo 2004). Furthermore, because human genetic variation is clinal, many individuals affiliate with two or more
continental groups. Thus, the genetically based “biogeographical ancestry” assigned to any given person generally will be broadly distributed and will be accompanied
by sizable uncertainties (Pfaff et al. 2004).
In many parts of the world, groups have mixed in
such a way that many individuals have relatively recent
ancestors from widely separated regions. Although genetic analyses of large numbers of loci can produce estimates of the percentage of a person’s ancestors coming
from various continental populations (Shriver et al. 2003;
Bamshad et al. 2004), these estimates may assume a false
distinctiveness of the parental populations, since human
groups have exchanged mates from local to continental
scales throughout history (Cavalli-Sforza et al. 1994;
Hoerder 2002). Even with large numbers of markers,
information for estimating admixture proportions of individuals or groups is limited, and estimates typically will
have wide CIs (Pfaff et al. 2004).
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Physical Variation in Humans
The distribution of many physical traits resembles the
distribution of genetic variation within and between human populations (American Association of Physical Anthropologists 1996; Keita and Kittles 1997). For example, ∼90% of the variation in human head shapes occurs
within every human group, and ∼10% separates groups,
with a greater variability of head shape among individuals with recent African ancestors (Relethford 2002).
A prominent exception to the common distribution of
physical characteristics within and among groups is skin
color. Approximately 10% of the variance in skin color
occurs within groups, and ∼90% occurs between groups
(Relethford 2002). This distribution of skin color and
its geographic patterning—with people whose ancestors
lived predominantly near the equator having darker skin
than those with ancestors who lived predominantly in
higher latitudes—indicate that this attribute has been
under strong selective pressure. Darker skin appears to
be strongly selected for in equatorial regions to prevent
sunburn, skin cancer, the photolysis of folate, and damage to sweat glands (Sturm et al. 2001; Rees 2003). A
leading hypothesis for the selection of lighter skin in
higher latitudes is that it enables the body to form greater
amounts of vitamin D, which helps prevent rickets (Jablonski 2004). However, the vitamin D hypothesis is not
universally accepted (Aoki 2002), and lighter skin in high
latitudes may correspond simply to an absence of selection for dark skin (Harding et al. 2000).
Because skin color has been under strong selective
pressure, similar skin colors can result from convergent
adaptation rather than from genetic relatedness. SubSaharan Africans, tribal populations from southern India, and Australian Aborigines have similar skin pigmentation, but genetically they are no more similar than
are other widely separated groups. Furthermore, in some
parts of the world in which people from different regions
have mixed extensively, the connection between skin color
and ancestry has been substantially weakened (Parra et
al. 2004). In Brazil, for example, skin color is not closely
associated with the percentage of recent African ancestors a person has, as estimated from an analysis of genetic variants differing in frequency among continent
groups (Parra et al. 2003).
Considerable speculation has surrounded the possible
adaptive value of other physical features characteristic
of groups, such as the constellation of facial features observed in many eastern and northeastern Asians (Guthrie
1996). However, any given physical characteristic generally is found in multiple groups (Lahr 1996), and demonstrating that environmental selective pressures shaped
specific physical features will be difficult, since such features may have resulted from sexual selection for indi-
Am. J. Hum. Genet. 77:519–532, 2005
viduals with certain appearances or from genetic drift
(Roseman 2004).
The Social Interpretation of Physical Variation
The Development of the “Ideology of Race”
Given our visual acuity and complex social relationships, humans presumably have always observed and
speculated about the physical differences among individuals and groups. But different societies have attributed markedly different meanings to these distinctions.
Classical civilizations from Rome to China tended to
invest much more importance in family or tribal affiliations than in physical appearance (Dikötter 1992; Goldenberg 2003). Some Roman writers adhered to an environmental determinism in which climate could affect
the appearance and character of groups (Isaac 2004).
But in many ancient civilizations, individuals with widely
varying physical appearances could become full members of a society by growing up within that society or
by adopting the society’s cultural norms (Snowden 1983;
Lewis 1990).
The English word “race” (possibly derived from the
Spanish raza, meaning “breed” or “stock”), along with
many of the ideas now associated with the term, were
products of the European era of exploration (Smedley
1999). As Europeans encountered people from different
parts of the world, they speculated about the physical,
social, and cultural differences between human groups.
The rise of the African slave trade, which gradually displaced an earlier trade in slaves from throughout the
world, created a further incentive to categorize human
groups to justify the barbarous treatment of African
slaves (Meltzer 1993). Drawing on classical sources and
on their own internal interactions—for example, the
hostility between the English and Irish was a powerful
influence on early thinking about the differences between
people (Takaki 1993)—Europeans began to sort themselves and others into groups associated with physical
appearance and with deeply ingrained behaviors and capacities. A set of “folk beliefs” took hold that linked
inherited physical differences between groups to inherited intellectual, behavioral, and moral qualities (Banton
1977). Although similar ideas can be found in other
cultures (Lewis 1990; Dikötter 1992), they appear not
to have had as much influence on social structures as
they did in Europe and the parts of the world colonized
by Europeans.
In the 18th century, the differences between human
groups became a focus of scientific investigation (Todorov 1993). Initially, scholars focused on cataloging
and describing “The Natural Varieties of Mankind,” as
Johann Friedrich Blumenbach entitled his 1775 text
(which established the five major divisions of humans
Race, Ethnicity, and Genetics Working Group: Racial and Ethnic Categories in Genetics
still reflected in some racial classifications). But as the
science of anthropology took shape in the 19th century,
European and American scientists increasingly sought
explanations for the behavioral and cultural differences
they attributed to groups (Stanton 1960). For example,
they measured the shapes and sizes of skulls and related
the results to group differences in intelligence or other
attributes (Lieberman 2001). Both before and after the
1859 publication of On the Origins of Species, a debate
raged in Europe over whether different human groups
had the same origin or were the product of separate
creations or evolutionary lineages (Wolpoff and Caspari
1997).
From the 17th through the 19th centuries, the merging
of folk beliefs about group differences with scientific explanations of those differences produced what one scholar
has called an “ideology of race” (Smedley 1999). According to this ideology, races are primordial, natural,
enduring, and distinct. Some groups might be the result
of mixture between formerly distinct populations, but
careful study can distinguish the ancestral races that had
combined to produce admixed groups.
The concept of race found wide application in many
societies. The eugenics movement of the late 19th and
early 20th centuries asserted as self-evident the biological
inferiority of particular groups (Kevles 1985). In many
parts of the world, the idea of race became a way of
rigidly dividing groups by use of culture as well as physical appearances (Hannaford 1996). Campaigns of oppression and genocide often used supposed racial differences to motivate inhuman acts against others (Horowitz
2001).
The Incongruities of Racial Classifications
Even as the idea of “race” was becoming a powerful
organizing principle in many societies, the shortcomings
of the concept were apparent. In the Old World, the
gradual transition in appearances from one group to
adjacent groups emphasized that “one variety of mankind does so sensibly pass into the other, that you cannot
mark out the limits between them,” as Blumenbach observed in his writings on human variation (Marks 1995,
p. 54). In parts of the Americas, the situation was somewhat different. The immigrants to the New World came
largely from widely separated regions of the Old World—
western and northern Europe, western Africa, and, later,
eastern Asia and southern Europe. In the Americas, the
immigrant populations began to mix among themselves
and with the indigenous inhabitants of the continent. In
the United States, for example, most people who selfidentify as African American have some European ancestors—in one analysis of genetic markers that have
differing frequencies between continents, European ancestry ranged from an estimated 7% for a sample of
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Jamaicans to ∼23% for a sample of African Americans
from New Orleans (Parra et al. 1998). Similarly, many
people who identify as European American have some
African or Native American ancestors, either through
openly interracial marriages or through the gradual inclusion of people with mixed ancestry into the majority
population. In a survey of college students who selfidentified as “white” in a northeastern U.S. university,
∼30% were estimated to have !90% European ancestry
(Shriver et al. 2003).
In the United States, social and legal conventions developed over time that forced individuals of mixed ancestry into simplified racial categories (Gossett 1997).
An example is the “one-drop rule” implemented in some
state laws that treated anyone with a single known African American ancestor as black (Davis 2001). The decennial censuses conducted since 1790 in the United
States also created an incentive to establish racial categories and fit people into those categories (Nobles 2000).
In other countries in the Americas where mixing among
groups was more extensive, social categories have tended
to be more numerous and fluid, with people moving into
or out of categories on the basis of a combination of
socioeconomic status, social class, ancestry, and appearance (Mörner 1967).
Efforts to sort the increasingly mixed population of
the United States into discrete categories generated many
difficulties (Spickard 1992). By the standards used in past
censuses, many millions of children born in the United
States have belonged to a different race than have one
of their biological parents. Efforts to track mixing between groups led to a proliferation of categories (such
as “mulatto” and “octoroon”) and “blood quantum”
distinctions that became increasingly untethered from
self-reported ancestry. A person’s racial identity can
change over time, and self-ascribed race can differ from
assigned race (Kressin et al. 2003). Until the 2000 census, Latinos were required to identify with a single race
despite the long history of mixing in Latin America;
partly as a result of the confusion generated by the distinction, 42% of Latino respondents in the 2000 census
ignored the specified racial categories and checked “some
other race” (Mays et al. 2003).
Ethnicity as a Way of Categorizing People
As the problems surrounding the word “race” became
increasingly apparent during the 20th century, the word
“ethnicity” was promoted as a way of characterizing the
differences between groups (Huxley and Haddon 1936;
Hutchinson and Smith 1996). Ethnicity typically emphasizes the cultural, socioeconomic, religious, and political
qualities of human groups rather than their genetic ancestry. It may encompass language, diet, religion, dress,
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customs, kinship systems, or historical or territorial identity (Cornell and Hartmann 1998).
However, as a way of understanding human groups,
ethnicity also suffers from several shortcomings. First,
ascribing an ethnic identity to a group can imply a much
greater degree of uniformity than is actually the case. In
the United States, the ethnic group “Hispanic or Latino”
contains such subgroups as Cuban Americans, Mexican
Americans, Puerto Ricans, and recent immigrants from
Central America (Hayes-Bautista and Chapa 1987). Combining these groups into a single category may serve useful bureaucratic or political ends but does not necessarily
result in a better understanding of these groups.
Also, ethnicity, like race, is a malleable concept that
can change dramatically in different times or circumstances (Waters 1990; Smelser et al. 2001). Ethnic groups
may come into existence and then dissipate as a result
of broad historical or social trends. Individuals might
change ethnic groups over the course of their lives or
identify with more than one group. A researcher, clinician, or government official might assign an ethnicity to
an individual quite different from the one that person
would acknowledge (Kressin et al. 2003).
Finally, despite attempts to distinguish “ethnicity” from
“race,” the two terms often are used interchangeably
(Oppenheimer 2001). Ethnic groups can share a belief
in a common ancestral origin (Cornell and Hartmann
1998), which also can be a defining characteristic of a
racial group. Furthermore, ethnic groups tend to promote marriage within the group, which creates an expectation of biological cohesion regardless of whether
that cohesion existed in the past.
Ancestry as a Way of Categorizing People
An alternative to the use of racial or ethnic categories
in genetics research is to categorize individuals in terms
of ancestry. Ancestry may be defined geographically (e.g.,
Asian, sub-Saharan African, or northern European), geopolitically (e.g., Vietnamese, Zambian, or Norwegian),
or culturally (e.g., Brahmin, Lemba, or Apache). The
definition of ancestry may recognize a single predominant source or multiple sources. Ancestry can be ascribed
to an individual by an observer, as was the case with
the U.S. census prior to 1960; it can be identified by an
individual from a list of possibilities or with use of terms
drawn from that person’s experience; or it can be calculated from genetic data by use of loci with allele frequencies that differ geographically, as described above.
At least among those individuals who participate in biomedical research, genetic estimates of biogeographical
ancestry generally agree with self-assessed ancestry (Tang
et al. 2005), but in an unknown percentage of cases,
they do not (Brodwin 2002; Kaplan 2003).
Despite its seemingly objective nature, ancestry also
Am. J. Hum. Genet. 77:519–532, 2005
has limitations as a way of categorizing people (Elliott
and Brodwin 2002). When asked about the ancestry of
their parents and grandparents, many people cannot provide accurate answers. In one series of focus groups in
the state of Georgia, 40% of ∼100 respondents said they
did not know one or more of their four grandparents
well enough to be certain how that person(s) would identify racially (Condit et al. 2003). Misattributed paternity
or adoption can separate biogeographical ancestry from
socially defined ancestry. Furthermore, the exponentially
increasing number of our ancestors makes ancestry a
quantitative rather than qualitative trait—5 centuries (or
20 generations) ago, each person had a maximum of 11
million ancestors (Ohno 1996). To complicate matters
further, recent analyses suggest that everyone living today has exactly the same set of genealogical ancestors
who lived as recently as a few thousand years in the
past, although we have received our genetic inheritance
in different proportions from those ancestors (Rohde et
al. 2004).
In the end, the terms “race,” “ethnicity,” and “ancestry” all describe just a small part of the complex web
of biological and social connections that link individuals
and groups to each other.
Racial, Ethnic, and Ancestral Categories in Genetics
Research
The Effects of Racial and Ethnic Identities on Health
Racial and ethnic groups can exhibit substantial average differences in disease incidence, disease severity,
disease progression, and response to treatment (LaVeist
2002). In the United States, African Americans have
higher rates of mortality than does any other racial or
ethnic group for 8 of the top 10 causes of death (Hummer et al. 2004). U.S. Latinos have higher rates of death
from diabetes, liver disease, and infectious diseases than
do non-Latinos (Vega and Amaro 1994). Native Americans suffer from higher rates of diabetes, tuberculosis,
pneumonia, influenza, and alcoholism than does the rest
of the U.S. population (Mahoney and Michalek 1998).
European Americans die more often from heart disease
and cancer than do Native Americans, Asian Americans,
or Hispanics (Hummer et al. 2004).
Considerable evidence indicates that the racial and
ethnic health disparities observed in the United States
arise mostly through the effects of discrimination, differences in treatment, poverty, lack of access to health
care, health-related behaviors, racism, stress, and other
socially mediated forces. The infant mortality rate for
African Americans is approximately twice the rate for
European Americans, but, in a study that looked at members of these two groups who belonged to the military
and received care through the same medical system, their
Race, Ethnicity, and Genetics Working Group: Racial and Ethnic Categories in Genetics
infant mortality rates were essentially equivalent (Rawlings and Weir 1992). Recent immigrants to the United
States from Mexico have better indicators on some measures of health than do Mexican Americans who are
more assimilated into American culture (Franzini et al.
2001). Diabetes and obesity are more common among
Native Americans living on U.S. reservations than among
those living outside reservations (Cooper et al. 1997).
Rates of heart disease among African Americans are associated with the segregation patterns in the neighborhoods where they live (Fang et al. 1998). Furthermore,
the risks for many diseases are elevated for socially, economically, and politically disadvantaged groups in the
United States, suggesting that socioeconomic inequities
are the root causes of most of the differences (Cooper
et al. 2003; Cooper 2004).
However, differences in allele frequencies certainly
contribute to group differences in the incidence of some
monogenic diseases, and they may contribute to differences in the incidence of some common diseases (Risch
et al. 2002; Burchard et al. 2003; Tate and Goldstein
2004). For the monogenic diseases, the frequency of
causative alleles usually correlates best with ancestry,
whether familial (for example, Ellis–van Creveld syndrome among the Pennsylvania Amish), ethnic (TaySachs disease among Ashkenazi Jewish populations), or
geographical (hemoglobinopathies among people with
ancestors who lived in malarial regions). To the extent
that ancestry corresponds with racial or ethnic groups
or subgroups, the incidence of monogenic diseases can
differ between groups categorized by race or ethnicity,
and health-care professionals typically take these patterns
into account in making diagnoses.
Even with common diseases involving numerous genetic variants and environmental factors, investigators
point to evidence suggesting the involvement of differentially distributed alleles with small to moderate effects.
Frequently cited examples include hypertension (Douglas et al. 1996), diabetes (Gower et al. 2003), obesity
(Fernandez et al. 2003), and prostate cancer (Platz et al.
2000). However, in none of these cases has allelic variation in a susceptibility gene been shown to account for
a significant fraction of the difference in disease prevalence among groups, and the role of genetic factors in
generating these differences remains uncertain (Mountain and Risch 2004).
The Allelic Architecture of Disease
The genetic architecture of common diseases is an important factor in determining the extent to which patterns of genetic variation influence group differences in
health outcomes (Reich and Lander 2001; Pritchard and
Cox 2002; Smith and Lusis 2002). According to the
common disease/common variant hypothesis, common
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variants present in the ancestral population before the
dispersal of modern humans from Africa play an important role in human diseases (Goldstein and Chikhi 2002).
Genetic variants associated with Alzheimer disease, deep
venous thrombosis, Crohn disease, and type 2 diabetes
appear to adhere to this model (Lohmueller et al. 2003).
However, the generality of the model has not yet been
established and, in some cases, is in doubt (Weiss and
Terwilliger 2000; Pritchard and Cox 2002; Cardon and
Abecasis 2003). Some diseases, such as many common
cancers, appear not to be well described by the common
disease/common variant model (Kittles and Weiss 2003;
Wiencke 2004).
Another possibility is that common diseases arise in
part through the action of combinations of variants that
are individually rare (Pritchard 2001; Cohen et al. 2004).
Most of the disease-associated alleles discovered to date
have been rare, and rare variants are more likely than
common variants to be differentially distributed among
groups distinguished by ancestry (Risch et al. 2002; Kittles and Weiss 2003). However, groups could harbor
different, though perhaps overlapping, sets of rare variants, which would reduce contrasts between groups in
the incidence of the disease.
The number of variants contributing to a disease and
the interactions among those variants also could influence the distribution of diseases among groups. The difficulty that has been encountered in finding contributory
alleles for complex diseases and in replicating positive
associations suggests that many complex diseases involve numerous variants rather than a moderate number
of alleles, and the influence of any given variant may
depend in critical ways on the genetic and environmental
background (Risch 2000; Weiss and Terwilliger 2000;
Altmüller et al. 2001; Hirschhorn et al. 2002). If many
alleles are required to increase susceptibility to a disease,
the odds are low that the necessary combination of alleles would become concentrated in a particular group
purely through drift (Cooper 2004).
Population Substructure in Genetics Research
One area in which racial and ethnic categories can be
important considerations in genetics research is in controlling for confounding between population substructure, environmental exposures, and health outcomes. Association studies can produce spurious results if cases
and controls have differing allele frequencies for genes
that are not related to the disease being studied (Cardon
and Palmer 2003; Marchini et al. 2004), although the
magnitude of this problem in genetic association studies
is subject to debate (Thomas and Witte 2002; Wacholder
et al. 2002). Various methods have been developed to
detect and account for population substructure (Morton
and Collins 1998; Hoggart et al. 2003), but these meth-
526
ods can be difficult to apply in practice (Freedman et al.
2004).
Population substructure also can be used to advantage
in genetic association studies. For example, populations
that represent recent mixtures of geographically separated ancestral groups can exhibit longer-range linkage
disequilibrium between susceptibility alleles and genetic
markers than is the case for other populations (Hoggart
et al. 2004; Patterson et al. 2004; Smith et al. 2004;
McKeigue 2005). Genetic studies can use this admixture
linkage disequilibrium to search for disease alleles with
fewer markers than would be needed otherwise. Association studies also can take advantage of the contrasting
experiences of racial or ethnic groups, including migrant
groups, to search for interactions between particular alleles and environmental factors that might influence
health (Chaturvedi 2001; Collins et al. 2003).
Conclusions
When deciding whether and how to use racial, ethnic,
and ancestral categories in research, geneticists face conflicting demands. On the one hand, many observers have
made powerful arguments in favor of reducing or even
eliminating the use of racial or ethnic categories in genetics research (Fullilove 1998; Goodman 2000; Lee et
al. 2001; Braun 2002; Duster 2003, 2005; Stevens 2003;
Kahn 2004; Sankar et al. 2004; Ossorio and Duster
2005). These observers point out that the use of these
categories reinforces the widespread impression that
health inequities arise through the action of genetic differences and independent of socially mediated mechanisms. In this way, genetics research that involves making population comparisons can inaccurately stereotype
racial and ethnic groups, both by implying that such
groups are clearly delineated and by associating health
outcomes with all individuals in those groups rather than
with only those individuals who exhibit the outcome.
Furthermore, according to critics, an overemphasis on
the genetic component of health differences shifts attention and resources away from established contributors
to health disparities—in particular, the differences in
treatment and socioeconomic disadvantages that disproportionately affect minority groups (Sankar et al. 2004).
Genetics research offers no evidence that any one group
is superior or inferior to any other, although some individuals continue to try to distort genetic findings to
buttress prejudiced outlooks. Biomedical research that
accentuates genetic differences among groups, say critics
of this research, is as conceptually flawed as the race
science of the 19th century (Bhopal 1997).
On the other hand, race and ethnicity are such prominent aspects of many societies that it is difficult, and
often inadvisable, to ignore them in genetics research.
The members of these groups can have widely disparate
Am. J. Hum. Genet. 77:519–532, 2005
economic, social, and psychological experiences and can
be exposed to very different environments as a consequence of their membership in a particular group. These
differential experiences and environmental exposures can
be used to investigate the biological mechanisms that
contribute to health disparities among groups (LaVeist
1996). In addition, self-identified race, ethnicity, or
ancestry can provide measures of population substructure that help avoid false-positive results in association
studies.
One way for geneticists to ease the dilemma they face
is to try to move beyond racial, ethnic, or ancestral categories in their work (Ota Wang and Sue 2005; Shields
et al. 2005). Rather than using racial, ethnic, or ancestral labels as proxies for much more detailed social,
economic, environmental, biological, or genetic factors,
researchers can try to measure these factors directly. For
example, controlling for socioeconomic status by use of
census tract data can substantially reduce the excess
mortality risk observed in disadvantaged minority populations (Krieger et al. 2005). Similarly, genotyping to
estimate biogeographical ancestry can be a better control for population substructure than self-identified race,
ethnicity, or ancestry (Shields et al. 2005).
When the use of racial or ethnic categories in research
is deemed necessary, researchers can avoid overgeneralization by using labels that are as specific as possible.
Today many genetic investigations label populations with
the same loose terms used by the public (Sankar and
Cho 2002; Clayton 2003; Collins 2004; Comstock et
al. 2004). But labels such as “Hispanic,” “Black,”
“Mexican American,” “White,” “Asian,” “European,”
or “African” can have ambiguous or contradictory
meanings among researchers, research subjects, and the
general public. Use of such broad labels without careful
definitions can impair scientific understanding and imply that distinctions between socially defined populations are genetically well established. Genetics researchers often rely on the categories specified in the U.S.
census—encouraged by regulations that urge diversity
of study populations—but these categories are used today mainly for administrative and social purposes and
were not designed for genetics research. Even when the
census categories are used to select research subjects to
ensure diversity, researchers can analyze their results
using more-specific labels that are closely tied to the
scientific questions being asked (Kaplan and Bennett
2003). For example, labels based on biogeographical
ancestry may be suited for many genetics studies, socially based labels may be more appropriate for health
disparities and clinical research, and both types of information may be valuable for studies of some geneenvironment interactions.
Individuals can be assigned to specific population categories in a number of ways, with the most appropriate
Race, Ethnicity, and Genetics Working Group: Racial and Ethnic Categories in Genetics
way, again, depending on the research question being
investigated (Foster and Sharp 2004; International HapMap Consortium 2004). Research subjects can be asked
to identify themselves with geographical or cultural
populations, which may be defined by the researcher or
by the local communities within which the research is
being conducted. Communities and researchers can
choose categories together through a consultative or engagement process between researchers and the community (Foster et al. 1999; Condit et al. 2002). Categorical
systems also can include the possibility of simultaneous,
multiple-group memberships in groups at higher or lower
levels of organization.
A number of journals, including Nature Genetics
(Anonymous 2000), Archives of Pediatrics & Adolescent Medicine (Rivara and Finberg 2001), and the British Medical Journal (Anonymous 1996), have separately
issued guidelines stating that researchers should carefully define the terms they use for populations, and some
journals have asked researchers to justify their use of
racial or ethnic groups in research. But enforcement of
these guidelines has been uneven, and compliance will
continue to be spotty without greater awareness among
researchers of the difficulties and risks involved in defining populations (Sankar and Cho 2002; Anonymous
2004).
Efforts to move past the use of racial and ethnic categories in genetics research often will require consideration of a very broad range of additional variables
(Chakravarti and Little 2003). These variables will differ from study to study, but even a partial list includes
racism and discrimination, socioeconomic status, social
class, personal or family wealth, environmental exposures, insurance status, age, diet and nutrition, health
beliefs and practices, educational level, language spoken, religion, tribal affiliation, country of birth, parents’
country of birth, length of time in the country of residence, and place of residence along with genetic variation (Kaplan and Bennett 2003). Research that successfully integrates such a wide range of variables will require the collaboration of individuals with many different disciplinary backgrounds (Bonham et al. 2005).
A particular challenge for interdisciplinary teams will
be designing their studies and reporting their results in
ways that convey to the public the complexities of biological systems (Weiss 1998; Clark 2002; Chakravarti
and Little 2003). Within the highly interconnected network of factors involved in complex diseases, the influence of any given allele likely will depend on past and
current biological and environmental contexts, which
often will make it difficult to demonstrate that a given
variant directly “causes” a particular condition (Weatherall 1999; Page et al. 2003). Growing appreciation of
the ways in which gestational influences (Sallout and
Walker 2003), childhood illnesses (Gluckman and Han-
527
son 2004), obesity (Calle and Kaaks 2004), exposure to
toxins (Whyatt et al. 2004), stress (Wallace et al. 2004),
and other factors influence later illnesses highlights the
multiple interconnections among biological mechanisms,
environmental influences, and chance events (Shostak
2003).
Despite this complexity, genetics researchers have a
unique opportunity to reduce at least some of the confusion and controversy surrounding the issues of race,
ethnicity, ancestry, and health. They can demonstrate
the irrelevance of racial and ethnic labels for pursuing
many research questions and health improvement objectives—for example, by clarifying the many ways in
which environmental factors that extend across groups
interact with biological processes to produce common
diseases (Lin and Kelsey 2000; Rotimi 2004). By emphasizing the close genetic affinities between members
of different groups, researchers can reduce the widespread misconception that substantial genetic differences
separate groups (Wilson et al. 2001; Olson 2002; Jorde
and Wooding 2004). As the complex origins of human
traits, behaviors, and diseases slowly are unraveled, how
genetics research is conducted could influence whether
racial and ethnic discrimination increases or decreases
over time.
Acknowledgments
The Race, Ethnicity, and Genetics Working Group of the
National Human Genome Research Institute appreciates the
valuable input received on earlier drafts of this paper from
Michael Bamshad, Wylie Burke, Mildred Cho, Troy Duster,
Sara Hull, Lynn Jorde, Jeff Long, Jeff Murray, and Ken Weiss.
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